Abstract |
Previous studies have shown that KA receptor subunit GluR6 mediated c-Jun N-terminal protein kinase (JNK) signaling is involved in global ischemia injury. Our present study indicates that focal ischemic brain insult on rat middle cerebral artery occlusion (MACo) model enhances the assembly of the GluR6-PSD95-MLK3 module and facilitates the phosphorylation of JNK. Most importantly, a peptide containing the TAT protein transduction sequence, Tat-GluR6-9c, can perturb the assembly of the GluR6-PSD95-MLK3 signaling module and suppress the activation of MLK3, MKK7/4 and JNK. As result, the inhibition of JNK activation caused by Tat-GluR6-9c diminishes the phosphorylation of the transcription factor c-Jun, down-regulates FasL expression and attenuates bax translocation, release of cytochrome c and the activation of caspase-3. Furthermore, MCAo induced infract volume is reduced by intracerebroventricular injection of Tat-Glur6-9c. Oxygen- glucose-deprivation (OGD) cultured cortical neuronal cell also shows an improved cell viability by application of Tat-GluR6-9c. Taken together, our findings strongly suggest that GluR6-PSD95-MLK3 signaling module mediated activation of nuclear and non-nuclear pathways of JNK activation are involved in focal ischemia injury and OGD. Tat-GluR6-9c, the peptide we constructed, gives a new insight into the therapy for ischemic stroke.
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Authors | Chang-Zhou Yu, Chong Li, Dong-Sheng Pei, Yan-Yan Zong, Qiong Shi, Xiang-Ru Wen, Qiu-Hua Guan, Dong Hang, Xiao-Yu Hou, Guang-Yi Zhang |
Journal | Neurochemical research
(Neurochem Res)
Vol. 34
Issue 11
Pg. 2008-21
(Nov 2009)
ISSN: 1573-6903 [Electronic] United States |
PMID | 19449206
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Disks Large Homolog 4 Protein
- Dlg4 protein, rat
- Gluk2 kainate receptor
- Intracellular Signaling Peptides and Proteins
- Membrane Proteins
- Neuroprotective Agents
- Receptors, Kainic Acid
- Recombinant Fusion Proteins
- tat Gene Products, Human Immunodeficiency Virus
- Glucose
- Oxygen
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Topics |
- Animals
- Cerebral Cortex
(cytology, metabolism)
- Disks Large Homolog 4 Protein
- Glucose
(deficiency)
- In Vitro Techniques
- Intracellular Signaling Peptides and Proteins
(metabolism)
- Ischemic Attack, Transient
(metabolism, prevention & control)
- Male
- Membrane Proteins
(metabolism)
- Mutation
- Neurons
(cytology, drug effects, metabolism)
- Neuroprotective Agents
(pharmacology, therapeutic use)
- Oxygen
(pharmacology)
- Rats
- Rats, Sprague-Dawley
- Receptors, Kainic Acid
(genetics, metabolism)
- Recombinant Fusion Proteins
(genetics, pharmacology, therapeutic use)
- tat Gene Products, Human Immunodeficiency Virus
(genetics)
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